Submissions for variant NM_001271208.2(NEB):c.61G>A (p.Glu21Lys) (rs199907781)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000733851	SCV000617818	uncertain significance	not provided	2017-10-19	criteria provided, single submitter	clinical testing	The c.61 G>A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.61 G>A variant is observed in 20/126,456 (0.02%) alleles from individuals of European background (Lek et al., 2016). Multiple in-silico splice prediction models predict that c.61 G>A enhances a cryptic splice donor site which may supplant the natural donor site and lead to abnormal gene splicing. However, in the absence of RNA/functional studies the actual effect of c.61 G>A on splicing in this individual is unknown. If c.61 G>A does not alter splicing, it will result in the E21K missense change. The E21K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. However, most reported pathogenic variants in the NEB gene are truncating/loss-of-function. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae	RCV000550343	SCV000640840	uncertain significance	Nemaline myopathy 2	2018-02-14	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid with lysine at codon 21 of the NEB protein (p.Glu21Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs199907781, ExAC 0.01%). This variant has not been reported in the literature in individuals with NEB-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000733851	SCV000861952	uncertain significance	not provided	2018-06-13	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000550343	SCV000993627	uncertain significance	Nemaline myopathy 2	2019-03-15	criteria provided, single submitter	research